Project Summary Rare and de novo mutations of genes confer significant risk for autism spectrum disorders (ASDs) and related Developmental Disorders (DDs). Among the most strongly-associated genes are synaptic receptors and related scaffolding proteins. These recent discoveries have illuminated key neurodevelopmental mechanisms underlying disease, in particular the involvement of glutamatergic signaling pathways. However, new therapeutic approaches based on gene discoveries have been slow to develop. We propose as a proof-of- principle to carry out a preclinical study focused on the treatment of a rare but potentially-treatable disorder caused by inactivating mutations of the AMPA receptor (AMPAR) trafficking protein CACNG2, also known as Stargazin (PMID:27018473, 21376300). Using a transgenic mouse model of a human de novo deletion identified previously (CACNG2?e2), we have confirmed that the human mutation of CACNG2 leads in deficits in AMPA receptor trafficking and behavior. The goal of this project is to characterize deficits in synaptic plasticity and behavior in CACNG2?e2 mice, and to restore glutamatergic signalingand cognitive function using the ampakine (AMPA receptor potentiator) CX1739. Aim 1: In CACNG2?e2 mice we will analyze the composition of AMPARs, directly measure synaptic plasticity in the hippocampus, and assess performance on a variety of behavioral tasks. Aim 2: We will seek to rescue physiological and behavioral deficits of CACNG2?e2 mice by sub-chronic treatment withCX1739 at two doses. This study will advance our understanding of how human genetic variation in CACNG2 can influence neurodevelopment and provide a proof of principle for a personalized treatment targeting a deficit in glutamatergic signaling.